The present invention relates to an excellent pharmaceutical preparation for prevention or treatment of the restenosis after percutaneous transluminal coronary angioplasty (PTCA) which comprises as an effective ingredient a prostaglandin analog, a pharmaceutically acceptable salt thereof or a hydrate thereof.
Since PG (hereinafter PG represents prostaglandin) exhibits various important physiological actions, the syntheses of a great number of the derivatives and the biological activities have been investigated and have been reported in many literatures, for example, Japanese Patent Kokai No. 52-100446 and U.S. Pat. No. 4,131,738.
PG and the derivatives thereof have biological actions such as a vasodilating action, a prophlogistic action, an inhibitory action of blood platelet aggregation, a uterine muscle contraction action, an intestine contraction action or a lowering action of intraocular pressure, and are useful for treatment or prevention of myocardial infarction, angina pectoris, arteriosclerosis, hypertension or duodenal ulcer, and further useful for labor induction, artificial termination of pregnancy, etc.
On the other hand, PTCA has low invasiveness to the patient as a therapeutic modality of ischemic heart diseases and has an excellent initial treatment effect, therefore, it is a plasty which recently has rapidly been developed. However, there has been an unsolved drawback of causing restenosis of coronary artery at a frequency of 30-40% within a few months after PTCA.
The compounds which can control not only the migration from intima to mesothelium of vascular smooth muscle cells deeply associating with the onset of restenosis but also their growth in the mesothelium are greatly expected as drugs for prevention of the restenosis. However, no clinically available drugs have been found.
An object of the present invention is to provide a pharmaceutical preparation for prevention or treatment of the restenosis after PTCA which exhibits an inhibiting action on the growth of vascular smooth muscle.
As a result of the continued extensive studies, the present inventors have found that a prostaglandin analog represented by the following Formula (I) exhibits a characteristic inhibiting action on the growth of vascular smooth muscle, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin analog represented by Formula (I): 
[wherein A is an ethylene group, a vinylene group or an ethynylene group, Y1 and Y2 are the same or different, and each a hydrogen atom, a halogen atom, a cyano group, a C1-3 aminoalkyl group, a C1-6 hydroxyalkyl group, NR5R6 (wherein R5 and R6 are the same or different, and each a hydrogen atom or a C1-6 alkyl group), a hydroxyl group, a C1-6 alkoxy group, a C1-9 alkyl group, a C1-6 alkyl group substituted with halogen(s) or a C1-5 acyl group, R1 and R2 are the same or different, and each a hydrogen atom, a halogen atom, a C1-9 alkyl group or a C1-6 alkyl group substituted with halogen(s), m is an integer of 0 to 6, and n is an integer of 0 to 3], a pharmaceutically acceptable salt thereof or a hydrate thereof.
In the present invention, the vinylene group means a cis- or trans-vinylene group.
The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.
The C1-3 aminoalkyl group means a straight or branched aminoalkyl group having 1 to 3 carbon atoms, examples of which are an aminomethyl group, an aminoethyl group and an aminopropyl group, and preferably an aminomethyl group.
Examples of the C4-8 cyclic amine are pyrrolidine, piperidine and morpholine, and preferably piperidine.
The C1-6 hydroxyalkyl group means a straight or branched hydroxyalkyl group having 1 to 6 carbon atoms, examples of which are a hydroxymethyl group, a dimethylhydoxymethyl group and a dihydroxymethyl group.
The C1-6 alkoxy group means a straight or branched alkoxy group having 1 to 6 carbon atoms, examples of which are a methoxy group, an ethoxy group and a propoxy group.
The C1-6 alkyl group substituted with halogen(s) means a straight or branched alkyl group having 1 to 6 carbon atoms which is substituted with fluorine atom(s), chlorine atom(s), bromine atom(s) or iodine(s), and is preferably a perfluoroalkyl group, and more preferably a trifluoromethyl group.
The C1-6 alkyl group means a straight or branched alkyl group having 1 to 6 carbon atoms, and examples of which are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a 2-ethylpropyl group, a hexyl group, an isohexyl group and a 1-ethylbutyl group.
The C1-9 alkyl group means the above-mentioned C1-6 alkyl group and a straight or branched C7-9 alkyl group means, example of which are a heptyl group, an octyl group and a nonyl group.
The C1-5 acyl group means a straight or branched alkanoyl, alkenoyl or alkynoyl group having 1 to 5 carbon atoms, examples of which are an acetyl group, a propionyl group, a crotonoyl group and a propioloyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metals (e.g., sodium or potassium), alkali earth metals (e.g., calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium or tris(hydroxymethyl)aminomethane.
When Y1 or Y2 is NR5R6, R5 and R6 are preferably each a methyl group.
The compounds of Formula (I) of the present invention can be specifically prepared, for example, by the methods summarized by the following reaction scheme. 
In the reaction scheme, TBS is a tert-butyldimethylsilyl group, Axe2x80x2 is an ethylene group or a vinylene group, Et is an ethyl group, A, Y1, Y2, R1, R2, m and n are as defined above.
The above-mentioned reaction scheme is illustrated as follows:
(1) At first, a known compound of Formula (II) is reacted with 0.8 to 2.0 equivalents of a compound represented by Formula (III) or (IV) in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride or n-hexane) at xe2x88x9278 to 30xc2x0 C. according to the method of Sato et al. (Journal of Organic Chemistry, vol. 53, page 5590 (1988)) to stereospecifically give a compound of Formula (V). Herein, the compound wherein A is an ethylene group or a vinylene group (i.e., the compound wherein A is Axe2x80x2) can be obtained by a reaction using a compound of Formula (III) at xe2x88x9278 to 0xc2x0 C., and the compound wherein A is an ethynylene group can be obtained by a reaction using a compound of Formula (IV) at 0 to 30xc2x0 C.
The organic copper compound of Formula (III) used as a material can be prepared, for example, according to a method shown by the following reaction scheme. 
In the reaction scheme, Axe2x80x2, R1, R2 and TBS are as defined above.
That is, an aldehyde compound represented by Formula (VIII) is reacted with methyl (triphenylphosphoranilidene)acetate in an inert solvent (e.g., methylene chloride, benzene, toluene or xylene) at 0xc2x0 C. to a reflux temperature of the solvent, followed by a reaction using a reductant such as diisobutylaluminum hydride to give a compound of Formula (IX).
Subsequently, the compound of Formula (IX) is subjected to a stereoselective oxidation reaction using diisopropyl L-(+)-tartrate and titanium tetraisopropoxide in tert-butyl hydroperoxide and methylene chloride at xe2x88x9220xc2x0 C. to give an epoxy compound. The resulting epoxy compound is subjected to methanesulfonylation and substitution with lithium chloride, successively, to give a compound of Formula (X).
The compound of Formula (X) is reacted with n-butyl lithium in tetrahydrofuran at xe2x88x9270xc2x0 C. to give an acetylene derivative, the hydroxyl group of which is then protected. in an ordinary manner, thereby a compound of Formula (XI) is obtained.
The compound of Formula (XI) is reacted in an amount of 0.5 to 4 equivalents with 1 to 5 equivalents of a radical reductant (e.g., trimethyltin hydride, tributyltin hydride or triphenyltin hydride) in the presence of 0.05 to 2 equivalents of a radical generating agent (e.g., azobisisobutyronitrile, azobiscyclohexanecarbonitrile, benzoyl peroxide or triethyl borane) at xe2x88x9278 to 100xc2x0 C., and then reacted with iodine in a mixture of diethyl ether and a saturated aqueous sodium bicarbonate solution to give a compound of Formula (XII).
The compound of Formula (XII) is subjected to a reaction with tert-butyl lithium and then subjected to a reaction with lithium 2-thienylcyanocuprate to give a compound of Formula (III).
(2) The compound of Formula (V) is reacted with 0.5 to 4 equivalents of an organic copper compound represented by Formula (VI) and 0.5 to 4 equivalents of trimethylchlorosilane in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane or n-pentane) at xe2x88x9278 to 40xc2x0 C., followed by hydrolysis using an inorganic acid (e.g., hydrochloric acid, sulfuric acid or nitric acid), an organic acid (e.g., acetic acid or p-toluenesulfonic acid) or an amine salt thereof (e.g., pyridinium p-toluenesulfonate) in an organic solvent (e.g., acetone, methanol, ethanol, isopropanol, diethyl ether or a mixture thereof) at 0 to 40xc2x0 C. to stereoselectively give a compound of Formula (VII).
Furthermore, the compound of Formula (V) is reacted with 0.5 to 4 equivalents of a compound represented by Formula (VIxe2x80x2), 0.05 to 2 equivalents of a radical generating agent (e.g., azobisisobutyronitrile, azobiscyclohexanecarbonitrile, benzoyl peroxide or triethyl borane) and 1 to 5 equivalents of a radical reductant (e.g., tributyltin hydride, triphenyltin hydride, dibutyltin hydride or diphenyltin hydride) in an inert solvent (e.g., benzene, toluene, xylene, n-hexane, n-pentane or acetone) at xe2x88x9278 to 100xc2x0 C. to give a compound of Formula (VII).
(3) The tert-butyldimethylsilyl group (i.e., a protective group of the hydroxyl group) of the compound of Formula (VII) is removed by using hydrofluoric acid, pyridinium poly(hydrogenfluoride) or hydrochloric acid under conventional conditions in a solvent (e.g., methanol, ethanol, acetonitrile, a mixture thereof or a mixture of these solvents and water) to give a PG analog of Formula (I) of the present invention.
The compounds of the present invention can be administered systemically or topically, or orally or parenterally such as rectally, subcutaneously, intramuscularly, intravenously or percutaneously, and preferably orally or intravenously. For example, they can be administered orally in the form such as tablets, powders, granules, dusting powders, capsules, solutions, emulsions or suspensions, each of which can be prepared according to conventional methods. As the dosage forms for intravenous administration, there are used aqueous or non-aqueous solutions, emulsions, suspensions or solid preparations to be dissolved in a solvent for injection immediately before use. Furthermore, the compounds of the present invention can be formulated into the form of inclusion compounds with xcex1-, xcex2- or xcex3-cyclodextrin, or methylated cyclodextrin. In addition, the compounds of the present invention can be administered by injection in the form of aqueous or non-aqueous solutions, emulsions, suspensions, etc. The dose is varied by the age, body weight, etc., but it generally is from 1 ng to 1 mg/day per adult, which can be administered in a single dose or divided doses.
Representative compounds of Formula (I) of the present invention are shown as follows.
The compounds of the present invention exhibit an excellent inhibiting action on the growth of vascular smooth muscle cells and have low side-effects, therefore, they are useful as a-drug for inhibition of vascular thickening (e.g. a cause of restenosis after percutaneous transluminal coronary angioplasty) and vascular occlusion, or useful as a drug for prevention or treatment of vascular thickening and vascular occlusion.
The present invention is illustrated in more details by the following examples and reference example, but it is not limited by these descriptions. In the nomenclature of the compound such as, for example, 2,3,4-trinor-1,5-inter-m-phenylene, xe2x80x9cnorxe2x80x9d means the lack of a carbon chain at the position of interest, (i.e., in the above case, it means the lack of carbon chains at the 2-, 3- and 4-positions), and xe2x80x9cinter-phenylenexe2x80x9d means the insertion of a benzene ring between the carbon atoms (i.e., in the above case, it means that each of the carbon atoms at the 1- and 5-positions binds to the benzene ring at the meta-position).
(1) To a methylene chloride solution (200 ml) of hydrocinnamaldehyde (25.64 g) was added methyl (triphenylphosphoranilidene)acetate (63.9 g) at 0xc2x0 C., followed by stirring at room temperature overnight. The insoluble substance was removed by filtration, the filtrate was concentrated, and the resulting residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=30:1) to give methyl (2E)-5-phenyl-2-pentenoate (30.22 g).
1H-NMR(200 MHz, CDCl3) xcex4 ppm: 2.44-2.60(m,2H), 2.72-2.84(m,2H), 3.72(s,3H), 5.85(dt,J=15.7,1.6 Hz,1H), 7.01(dt,J=15.7,6.8 Hz,1H), 7.12-7.37(m,5H)
IR(neat):3063,3028,2949,2858,1724,1658,1604,1497,1455,1436, 1320,1237,1203,1151,1088,1041,979,913,854,750,700 cmxe2x88x921 
(2) To a diethyl ether solution (200 ml) of the compound obtained in the above (1) (19.37 g) was added diisobutylaluminum hydride (1.5 M, toluene solution, 149.4 ml) at xe2x88x9270xc2x0 C., followed by stirring at room temperature for 1.5 hours. The mixture was made acidic with hydrochloric acid with ice-cooling, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the resulting crude product was evaporated under reduced pressure to give (2E)-5-phenyl-2-penten-1-ol (13.9 g).
b.p.91.5xcx9c92.0xc2x0 C./0.56 torr.
1H-NMR(200 MHz, CDCl3) xcex4 ppm: 1.20-1.60(br s,1H), 2.30-2.44(m,2H), 2.69(d,J=8.4 Hz,1H), 2.72(d,J=9.5 Hz,1H), 4.08(d,J=4.6 Hz,2H), 5.57-5.83(m,2H), 7.12-7.36(m,5H)
IR(neat):3339,3027,2927,2857,1964,1873,1806,1670,1604,1496, 1455,1385,1221,1155,1084,1000,970,747,699 cmxe2x88x921 
(3) To a mixture of powder Molecular Sieves 4A (8.2 g), titanium tetraisopropoxide (5.1 ml) and methylene chloride (125 ml) was added dropwise diisopropyl L-(+)-tartrate (4.4 ml) under an argon stream at xe2x88x9220xc2x0 C., followed by stirring under the same conditions for 30 minutes. Then, a methylene chloride solution (41 ml) of the compound obtained in the above (2) (13.9 g) was added and stirred at xe2x88x9220xc2x0 C. for an hour. The mixture was cooled to xe2x88x9230xc2x0 C., and tert-butyl hydroperoxide (3.2 M, methylene chloride solution, 48.3 ml) was added dropwise over 30 minutes. After the completion of the addition, stirring was continued at xe2x88x9220xc2x0 C. for 18 hours, and dimethyl sulfide (14 ml) was added, followed by stirring at the same temperature for 3 hours. Then, an aqueous tartaric acid solution (10%, 9.3 ml) was added, successively followed by stirring at room temperature for an hour, addition of sodium fluoride (60 g), stirring for an hour, addition of Celite (34 g) and diethyl ether (96 ml), and stirring for an hour. Filtration and concentration gave an oily substance (41.9 g), which was then dissolved in diethyl ether (109 ml), and an aqueous sodium hydroxide solution (1N, 60 ml) was added, followed by stirring at room temperature for 1.5 hours. The organic layer was separated, the aqueous layer was extracted with diethyl ether, and the organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1) to give (2S,3S)-2,3-epoxy-5-phenyl-1-pentanol (14.2 g).
1H-NMR(200 MHz, CDCl3) xcex4 ppm: 1.70(dd,J=7.4,5.6 Hz,1H), 1.83-1.98(m,2H), 2.64-2.93(m,3H), 2.99(dt,J=2.6 Hz,5.8 Hz,1H), 3.56(ddd,J=12.6,7.4,4.4 Hz,1H), 3.84(ddd,J=12.6,5.6,2.6 Hz,1H), 7.14-7.36(m,5H)
IR(neat):3401,3027,2928,2862,1603,1496,1455,1203,1093,1029, 989,880,751,701 cmxe2x88x921 
(4) To a methylene chloride solution (150 ml) of the compound obtained in the above (3) (14.1 g) and methanesulfonyl chloride (6.8 ml) was added dropwise triethylamine (13.3 ml) with ice-cooling. After the addition, the mixture was stirred at room temperature for 30 minutes, and washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give (2S,3S)-2,3-epoxy-1-methanesulfonyloxy-5-phenylpentane (20.0 g).
1H-NMR(200 MHz, CDCl3) xcex4 ppm : 1.84-1.99(m,2H), 2.64-3.02(m,4H), 3.04(s,3H), 4.05(dd,J=11.9,6.2 Hz,1H), 4.39(dd,J=11.9,2.9 Hz,1H), 7.13-7.37(m,5H)
IR(neat):3027,2940,1603,1496,1455,1358,1176,958,816,702, 529 cmxe2x88x921 
(5) An N,N-dimethylformamide solution (110 ml) of the compound obtained in the above (4) (19.5 g) and lithium chloride (6.44 g) was stirred under an argon stream with heating at 55xc2x0 C. for 2.5 hours. After cooling, water (35 ml) and a saturated aqueous sodium chloride solution (105 ml) were added and, after extraction with ethyl acetate: hexane (1:1), the organic layer was washed with an saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the resulting residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=20:1) to give (2R,3S)-l-chloro-2,3-epoxy-5-phenylpentane (14.2 g).
1H-NMR(200 MHz, CDCl3) xcex4 ppm : 1.82-1.98(m,2H), 2.62-3.01(m,4H), 3.45(dd,J=11.8,5.0 Hz,1H), 3.54(dd,J=11.8,5.8 Hz,1H), 7.14-7.36(m,5H)
IR(neat):3063,3027,2989,2945,2861,1604,1496,1455,1428,1385, 1266,1180,1031,923,875,751,731,700 cmxe2x88x921 
(6) To a tetrahydrofuran solution (67 ml) of the compound obtained in the above (5) (13.5 g) was added dropwise n-butyl lithium (2.5 M, hexane solution, 82.4 ml) under an argon stream at xe2x88x9270xc2x0 C. After the addition, stirring was continued under the same conditions for 30 minutes, and a saturated aqueous ammonium chloride solution (84 ml) was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated, and the resulting crude product was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1) to give (3S)-5-phenyl-1-pentyn-3-ol (10.96 g).
1H-NMR(200 MHz, CDCl3) xcex4 ppm : 1.94-2.14(m,2H), 2.50(d,J=2.2 Hz,1H), 2.74-2.86(m,2H), 4.28-4.44(m,1H), 7.12-7.36(m,5H)
IR(neat):3294,3063,3027,2929,2863,2115,1604,1497,1455,1044, 1013,747,700 cmxe2x88x921 
(7) To an N,N-dimethylformamide solution (67 ml) of the compound obtained in the above (6) (10.9 g) and imidazole (9.3 g) was added tert-butyldimethylchlorosilane (12.3 g) with ice-cooling, followed by stirring at room temperature overnight. The mixture was poured into a saturated aqueous sodium bicarbonate solution (300 ml), followed by stirring at room temperature for 15 minutes. After extraction with hexane, the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was evaporated under reduced pressure to give (3S)-3-(tert-butyldimethylsiloxy)-5-phenyl-1-pentyne (16.2 g).
b.p.108xc2x0 C./1.8 torr.
1H-NMR(200 MHz, CDCl3) xcex4 ppm : 0.10(s,3H), 0.13(s,3H), 0.91(s,9H), 1.90-2.08(m,2H), 2.75(d,J=9.5 Hz,1H), 2.78(d,J=9.2 Hz,1H), 4.37(dt,J=2.0 Hz,6.3 Hz, 1H), 7.11-7.35(m,5H)
IR(neat):3309,2955,2930,2858,2113,1605,1497,1472,1463,1387, 1362,1253,1095,1006,977,940,837,778,699 cmxe2x88x921 
(8) A mixture of the compound obtained in the above (7) (34.27 g), tributyltin hydride (50 g) and azobisisobutyronitrile (20 mg) was stirred under an argon stream at 160xc2x0 C. for an hour. After cooling to room temperature, evaporation under reduced pressure gave the crude product (75.8 g).
(9) To a mixture of the compound obtained in the above (8) (75.8 g), diethyl ether (496 ml) and a saturated aqueous sodium chloride solution (496 ml) was added dropwise a tetrahydrofuran solution (20 ml) of iodine (37.43 g) at 0xc2x0 C. After the addition, the mixture was stirred at the same temperature for 30 minutes, and an aqueous sodium thiosulfate solution was added, followed by extraction with hexane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The resulting residue was dissolved in methylene chloride (670 ml), and potassium fluoride (38.92 g) and water (12.1 ml) were added, followed by vigorously stirring at room temperature for an hour. Anhydrous magnesium sulfate was added and, after filtration, concentration gave the residue, which was then evaporated under reduced pressure to give the title compound (29.8 g).
b.p. 130-140xc2x0 C./0.60 torr.
1H-NMR(CDCl3,200 MHz) xcex4 ppm ;0.03(s,3H), 0.05(s,3H), 0.91(s,9H), 1.72-1.90(m,2H), 2.54-2.73(m,2H), 4.07-4.21(m,1H), 6.24(dd,J=14.4,1.1 Hz,1H), 6.56(dd,J=14.4,6.0 Hz,1H), 7.11-7.34(m,5H)